It has so far been suggested that in diseases accompanied with an abnormal accumulation of collagen (hepatic and pulmonary fibroses, keloid, hypertrophic scar, scleroderma, fibrosis in the scalp, or the like), synthesis and decomposition of collagen have been unbalanced.
For example, hepatic fibrosis accompanied with hepatic cirrhosis arises from an increase of collagen biosynthesis [Science, Vol. 176, P. 795, (1972)]or a decrease of collagenolytic activity [Biochemical Journal, Vol. 118, p. 229 (1970) and Life Sciences, Vol. 30, p. 1379, (1982)].
Alternatively, it has been known that in the scalp of androgenic alopecia, synthesis and decomposition of collagen are unbalanced, resulting in an abnormal accumulation of collagen, whereby fibrosis of the scalp is promoted [Hair Research, p. 244 (1981), edited by Orfanos, Montagna, Stuttgen, Springer-Verlag Berlin Heidelberg]. In consequence, it is assumed that tensing and a decrease of blood circulation of the scalp, deactivation of hair matrix cells or the like occurs to induce alopecia.
The decrease of the collagenolytic activity has been assumed to be caused by a decreased collagenase activity in each organ and/or skin fibroblasts [Journal of Clinical Investigation, Vol. 56, p. 1175 (1975)], so that an enhancement of a collagenase activity has been desired. This has been pointed out in medical treatments of, for example, hepatic cirrhosis.
Alternatively, metabolism of skin collagen is decreased not only by diseases as mentioned above but also by aging, whereby the collagen remains in the body for a long time and is subjected to a chemical modification to promote crosslinking thereof. It has been known that there is formed a vicious circle such that the collagen thus loses its function as an anchorage for cells with the consequence that collagen metabolism is further decreased. Accordingly, it has been said that aging of skin may be prevented by restraining the decrease in the collagen metabolism as well as preventing the formation of crosslinkages in collagen.
In order to sever such a vicious circle of the decrease in the collagen metabolism, it is required for collagen not to stay long in the body. For this purpose, an enhancement of the collagenase activity has been strongly desired.
The collagenase is a rate limiting enzyme acting during decomposing interstitial collagens (type-I, type-II and type-III collagens) in connective tissues, which plays an important role in collagen metabolism.
The collagenase is produced as a precursor, i.e., procollagenase that is secreted from cells and assumed to be activated in vivo by a protease such as plasmin, stromelysin or the like [Biochemical Journal, Vol. 166, p. 21 (1977) and Proceedings of the National Academy of Sciences of the U.S.A., Vol. 86, p. 2632 (1989)].
From the above, a substance to promote the production of the procollagenase, namely, a collagen metabolism ameliorant, is considered to be efficacious, in medical treatment, against diseases accompanied with an abnormal accumulation of collagen or, in amelioration of collagen metabolism, against collagen hypometabolism caused by aging.